University of Iowa researchers have shown for the first time that gene therapy
delivered to the brains of living mice can prevent the physical symptoms
and neurological damage caused by an inherited neurodegenerative disease
that is similar to Huntington's disease (HD).

If the therapeutic approach can be extended to humans, it may provide a
treatment for a group of incurable, progressive neurological diseases called
polyglutamine-repeat diseases, which include HD and several spinocerebellar
ataxias. The study, conducted by scientists at the UI Roy J. and Lucille
A. Carver College of Medicine and colleagues at the University of Minnesota
and the National Institutes of Health (NIH), appears in the August issue
of Nature Medicine and in the journal's advanced online publication July
4.

"This
is the first example of targeted gene silencing of a disease gene in the
brains of live animals and it suggests that this approach may
eventually be useful for human therapies," said senior study author
Beverly Davidson, Ph.D., (left) the Roy J. Carver Chair in Internal Medicine
and UI professor of internal medicine, physiology and biophysics, and neurology. "We
have had success in tissue culture, but translating those ideas to animal
models of disease has been a barrier. We seem to have broken through that
barrier."

Davidson and her colleagues used a viral vector (a stripped-down virus)
to deliver small fragments of genetic material (RNA) to critical brain cells
of mice with a disorder that mimics the human neurodegenerative disease spinocerebellar
ataxia 1 (SCA1). The genetic material suppresses the disease-causing SCA1
gene in a process known as RNA interference.

Mice with the SCA1 gene that were treated with the gene therapy had normal
movement and coordination. The gene therapy also protected brain cells from
the destruction normally caused by the disease and prevented the build-up
of protein clumps within the cells. In contrast, mice with the SCA1 disease
gene that were not treated developed movement problems and lost brain cells
in a manner similar to humans with this condition.

Both SCA1 and Huntington's disease are members of a group of neurodegenerative
disorders caused by a particular type of genetic flaw. In these dominantly
inherited diseases, a single mutated gene inherited from either parent produces
a protein that is toxic to cells. Thus, a successful therapy must remove
or suppress the disease-gene rather than simply add a corrected version.

"Although we know how to put genes into cells, the difficulty we face
in treating dominant diseases is how to remove or silence genes," Davidson
explained. "With our approach we can marry our gene therapy research
using viral vectors with RNA interference."

Silencing the SCA1 gene with RNA interference inhibited the production of
a neurotoxic protein, suggesting that this technology may also be helpful
against other degenerative neurological diseases caused by neurotoxic proteins,
such as Alzheimer's disease.

In addition to the finding that RNA interference inhibited gene expression
to such an extent that it protected the animals against the disease, another
important finding was that RNA interference in and of itself does not appear
to be toxic to normal brain cells. In the UI study, neither animal behavior
nor brain structures were adversely affected by RNA interference gene therapy.

Furthermore, the study revealed that specific properties of different gene
therapy vectors can be used to target those cells that are most involved
in causing the disease symptoms. In this case, the UI team proved that their
gene therapy vector, adeno-associated virus 1, specifically targeted Purkinje
cells, which are very important for gait and coordination.

"Choosing the right vector for the right cells could help us limit
gene expression to those cells where altering expression will have a beneficial
effect," Davidson explained.

Davidson is optimistic about the potential for using RNA interference gene
therapy to treat neurological diseases like HD and spinocerebellar ataxias
in humans.

"This is among the most important work I have done and I am excited
about the prospect of helping to move this approach into clinical trials," she
added.

In addition to Davidson, the team included UI researchers: Haibin Xia, Ph.D.,
and Qinwen Mao, Ph.D., who were co-lead authors of the study; Henry Paulson,
M.D., Ph.D.; Steven Eliason; Scott Harper, Ph.D.; and Inês Martins.
Harry Orr, Ph.D., at the University of Minnesota, and Linda Yang and Robert
Kotin, Ph.D., at the NIH also were part of the team.

Davidson first presented these findings at the American Society of Gene
Therapy meeting in June, where it was nominated the top abstract.

The study was funded in part by the NIH, the Hereditary Disease Foundation
and the Roy J. Carver Charitable Trust.

University of Iowa Health Care describes the partnership between the UI
Roy J. and Lucille A. Carver College of Medicine and UI Hospitals and Clinics
and the patient care, medical education and research programs and services
they provide. Visit UI Health Care online at www.uihealthcare.com.